Faculty Collaboration Database

T Cell-Intrinsic Interferon Regulatory Factor 1 Expression Suppresses Differentiation of CD4⁺ T Cell Populations That Support Chronic Gammaherpesvirus Infection. J Virol 2021 Sep 27;95(20):e0072621

Date

08/05/2021

Pubmed ID

34346769

Pubmed Central ID

PMC8475519

DOI

10.1128/JVI.00726-21

Scopus ID

2-s2.0-85116357074 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation. The host and viral factors that impact the gammaherpesvirus-driven germinal center response are not clearly defined. We show that the global expression of the antiviral and tumor suppressor interferon regulatory factor 1 (IRF-1) selectively attenuates the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and restricts the expansion of the latent viral reservoir. In this study, we found that T cell-intrinsic IRF-1 expression recapitulates some aspects of the antiviral state imposed by IRF-1 during chronic MHV68 infection, including the attenuation of the germinal center response and viral latency in the spleen. We also discovered that global and T cell-intrinsic IRF-1 deficiency leads to an unhindered rise of interleukin-17A (IL-17A)-expressing and follicular helper T cell populations, two CD4⁺ T cell subsets that support chronic MHV68 infection. Thus, this study unveils a novel aspect of the antiviral activity of IRF-1 by demonstrating IRF-1-mediated suppression of specific CD4⁺ T cell subsets that support chronic gammaherpesvirus infection. IMPORTANCE Gammaherpesviruses infect over 95% of the adult population, last the lifetime of the host, and are associated with multiple cancers. These viruses usurp the germinal center response to establish lifelong infection in memory B cells. This manipulation of B cell differentiation by the virus is thought to contribute to lymphomagenesis, although exactly how the virus precipitates malignant transformation in vivo is unclear. IRF-1, a host transcription factor and a known tumor suppressor, restricts the MHV68-driven germinal center response in a B cell-extrinsic manner. We found that T cell-intrinsic IRF-1 expression attenuates the MHV68-driven germinal center response by restricting the CD4⁺ T follicular helper population. Furthermore, our study identified IRF-1 as a novel negative regulator of IL-17-driven immune responses, highlighting the multifaceted role of IRF-1 in gammaherpesvirus infection.

Author List

Jondle CN, Johnson KE, Mboko WP, Tarakanova VL

Author

Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
B-Lymphocytes
CD4-Positive T-Lymphocytes
Cell Differentiation
Female
Gammaherpesvirinae
Germinal Center
Herpesviridae Infections
Host-Pathogen Interactions
Interferon Regulatory Factor-1
Interleukin-17
Lymphocyte Activation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Spleen
T-Lymphocytes, Helper-Inducer
Virus Latency